In the Veterans Healthcare System, aging men with testosterone deficiency and men on androgen depletion therapy for prostate cancer are at increased risk of developing type 2 diabetes (T2D). Although studies examining this issue have focused on the role of testosterone deficiency as a risk factor for insulin resistance, this approach ignores the role of testosterone deficiency as a potential cause of pancreatic ??cell dysfunction in men. Although it has been established that testosterone action is mediated via the androgen receptor (AR) -a ligand-activated transcription factor- the role of the AR in ?-cell dysfunction in T2D is unknown. There is tremendous potential for therapeutic application of novel work that addresses androgen deficiency in the context of T2D in large segments of aging men. The new far-reaching preliminary data from our laboratory show that male mice with conditional deletion of the AR in ?-cells (?ARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) and develop ?-cell failure to compensate for high fat diet- induced insulin resistance. The insulinotropic function of the testosterone-AR axis is present in cultured male human islets. Most importantly, in ?-cells, the AR is extranuclear, and the stimulatory effect of AR on GSIS involves cAMP generation and protein kinase A (PKA) activation. Finally, testosterone amplifies glucagon-like peptide-1 (GLP-1) enhancement of GSIS in rodent islets. Accordingly, the aims of this application are: 1) To explore a novel paradigm in which testosterone action on AR enhances GLP-1 action in ?-cells and 2) To elucidate the molecular determinants that maintain AR in an extranuclear compartment of ?-cells that amplify GLP-1 receptor action. The knowledge that will be generated by this grant will fill key gaps in our understanding of the fundamental mechanism of ?-cell dysfunction in men. This information will provide the foundation for development of approaches to modulate AR in a tissue-specific manner to prevent diabetes without prostate or cardiovascular side effects. Thus, the proposed work will have major scientific impact and open clinically relevant avenues for the Veterans Healthcare System population.